Heterocyclic compounds

ABSTRACT

Compounds of formula I:  
                 
and pharmaceutically-acceptable salts thereof, wherein Ar and R are as defined in the specification, compositions containing such compounds and the use of such compounds and compositions for use in therapy.

TECHNICAL FIELD

This invention relates to novel spiroazabicyclic heterocyclic amines orpharmaceutically acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

The use of compounds which bind to nicotinic acetylcholine receptors forthe treatment of a range of disorders involving reduced cholinergicfunction such as Alzheimer's disease, cognitive or attention disorders,anxiety, depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease is discussed inMcDonald et al., (1995) “Nicotinic Acetylcholine Receptors: MolecularBiology, Chemistry and Pharmacology”, Chapter 5 in Annual Reports inMedicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego,Calif.; and in Williams et al., (I 994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

DESCRIPTION OF THE INVENTION

This invention comprises compounds that are potent ligands for nicotinicacetylcholine receptors (nAChR's).

Compounds of the invention are those in accord with formula I:

and pharmaceutically-acceptable salts thereof, wherein:

Ar is either a monocyclic 5-membered ring heterocycle or a bicyclicbenzo-fused 5-membered ring heterocycle connected via the 5-memberedring, having, as part of the five membered ring one ring nitrogen atomand either one ring oxygen atom or one ring sulfur atom, said monocyclicor fused bicyclic ring heterocycle being substituted with 0, 1, or 2substitutents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ halogenatedalkyl, C₁₋₄ oxygenated alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halogen, —CO₂R¹,—C(O)R¹, —CN, —NO₂, —(CH₂)_(n)NR¹R²

n is 0, 1,or2

R¹ and R² are independently selected at each occurrence from hydrogen orC₁₋₄alkyl

R is a substitutent selected from hydrogen, C₁₋₄alkyl, C₁₋₄ halogenatedalkyl, C₁₋₄ oxygenated alkyl, or halogen.

Particular compounds of the invention are those wherein R is hydrogenand Ar is a 5-membered ring heterocycle having one ring nitrogen atomand either one ring oxygen atom or one ring sulfur atom and having 0 or1 substituents selected from methyl, ethyl, or halogen.

Other particular compounds of the invention are those wherein R ishydrogen and Ar is a 9-membered ring fused bicyclic heterocycle havingone ring nitrogen atom and either one ring oxygen atom or one ringsulfur atom and having 0 or 1 substituents selected from methyl, ethyl,or halogen.

Particular compounds of the invention include:

-   (2′R)-5′-(thiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3′,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(thiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine);-   (2′R)-5′-(thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2-methylthiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(benzothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(oxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(benzoxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(3,5-dimethylisoxazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].

Other particular compounds of the invention include:

-   (2′R)-5′-(2-trifluoromethylthiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2-methylthiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2-trifluoromethylthiazol-5-yl)spiro    [1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].

In another aspect the invention relates to compounds according toformula I and their use in therapy and compositions containing them.

In a further aspect the invention relates to compounds according toformula I wherein one or more of the atoms is labelled with aradioisotope of the same element. In a particular form of this aspect ofthe invention the compound of formula I is labelled with tritium

In a particular aspect the invention relates to the use of compoundsaccording to formula I for the therapy of diseases mediated through theaction of nicotinic acetylcholine receptors. A more particular aspect ofthe invention relates to the use of compounds of formula I for thetherapy of diseases mediated through the action of (x7 nicotinicacetylcholine receptors.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound as described above, and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment of prophylaxis of human diseases orconditions in which activation of the α7 nicotinic receptor isbeneficial.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment or prophylaxis of psychoticdisorders or intellectual impairment disorders.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment or prophylaxis of Alzheimer'sdisease, learning deficit, cognition deficit, attention deficit, memoryloss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia,or mania or manic depression Parkinson's disease, Huntington's disease,Tourette's syndrome, neurodegenerative disorders in which there is lossof cholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,craving, pain, and for ulcerative colitis.

Another aspect of the invention relates to a use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of human diseases or conditions in which activation of theα7 nicotinic receptor is beneficial.

Another aspect of the invention relates to a use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of psychotic disorders or intellectual impairment disorders.

Another aspect of the invention relates to the above use, wherein thecondition or disorder is Alzheimer's disease, learning deficit,cognition deficit, attention deficit, memory loss, Attention DeficitHyperactivity Disorder.

Another aspect of the invention relates to the above use, wherein thedisorder is anxiety, schizophrenia, or mania or manic depression.

Another aspect of the invention relates to the above use, wherein thedisorder is Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.

Another aspect of the invention relates to the use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,craving, pain, and for ulcerative colitis.

Another aspect of the invention relates to a method of treatment orprophylaxis of human diseases or conditions in which activation of theα7 nicotinic receptor is beneficial which comprises administering atherapeutically effective amount of a compound as described above.

Another aspect of the invention relates to a method of treatment orprophylaxis of psychotic disorders or intellectual impairment disorders,which comprises administering a therapeutically effective amount of acompound as described above.

Another aspect of the invention relates to the above method, wherein thedisorder is Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, or Attention Deficit HyperactivityDisorder.

Another aspect of the invention relates to the above method, wherein thedisorder is Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.

Another aspect of the invention relates to the above method, wherein thedisorder is anxiety, schizophrenia or mania or manic depression.

Another aspect of the invention relates to a method of treatment orprophylaxis of jetlag, cessation of smoking, nicotine addiction,craving, pain, and for ulcerative colitis, which comprises administeringa therapeutically effective amount of a compound as described above.

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and an inert pharmaceuticallyacceptable carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg/kg of animal body weight.Such doses may be given in divided doses 1 to 4 times a day or insustained release form. For man, the total daily dose is in the range offrom 5 mg to 1,400 mg, more preferably from 10 mg to 100 mg, and unitdosage forms suitable for oral administration comprise from 2 mg to1,400 mg of the compound admixed with a solid or liquid pharmaceuticalcarrier or diluent.

The compounds of formula I, or an enantiomer thereof, andpharmaceutically acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inert pharmaceuticallyacceptable diluent or carrier.

Examples of diluents and carriers are:

-   -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   for capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the below mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically acceptable salt thereof, to apatient.

Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α7 nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α4 nAChRsubtype. Therefore, compounds which are selective for the α7 nAChRsubtype are preferred. The compounds of the invention are indicated aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania and manic depression,and anxiety. Examples of intellectual impairment disorders includeAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, and Attention Deficit Hyperactivity Disorder. Thecompounds of the invention may also be useful as analgesics in thetreatment of pain (including chronic pain) and in the treatment orprophylaxis of Parkinson's disease, Huntington's disease, Tourette'ssyndrome, and neurodegenerative disorders in which there is loss ofcholinergic synapses. The compounds may further be indicated for thetreatment or prophylaxis of jetlag, for use in inducing the cessation ofsmoking, craving, and for the treatment or prophylaxis of nicotineaddiction (including that resulting from exposure to products containingnicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis.

As used herein, the term “C₁₋₄ alkyl” refers to a straight-chained,branched, or cyclic C₁₋₄alkyl group.

As used herein the term “C₁₋₄ halogenated alkyl” refers to a C₁₋₄alkylgroup substituted ls with 1, 2, or 3 halogen atoms.

As used herein the term “C₁₋₄ oxygenated alkyl” refers to a C₁₋₄hydroxyalkyl or C₁₋₄ alkoxyalkyl group.

Methods of Preparation

Methods which may be used for the synthesis of compounds of formula Iinclude the method outlined in Scheme 1. Unless otherwise noted Ar and Rin Scheme 1 are as defined above for Formula 1.

Compounds of formula I may be prepared from compounds of formula IIwherein X represents a halogen or OSO₂CF₃ substituent by reaction withan appropriate organometallic compound of formula III in the presence ofa suitable organometallic catalyst and solvent. Suitable compounds offormula III include boronic acids, in which M represents B(OH)₂, boronicacid esters, in which M represents B(OY)₂ , where Y represents asuitable acyclic or cyclic alkyl or aryl group, and organotin compounds,in which M represents a suitable trialkylstannyl group, for exampletrimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium (0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylideneacetone)dipalladium(0) and a suitable triarylphosphineor triarylarsine ligand, for example triphenylphosphine,tri(o-tolyl)phosphine or triphenylarsine. Suitable solvents includeinert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran,or 1,4-dioxane, or alcohols, such as ethanol, or mixtures thereof. Ifthe compound of formula III is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Certain compounds of formula II wherein X represents halogen may beprepared from compounds of formula II wherein X represents hydrogen byreaction with a suitable halogenating agent in a suitable solvent.Suitable halogenating agents include bromine. Suitable solvents includeacetic acid. The reaction is preferably performed at a temperature of0-50 ° C., and most preferably at a temperature of 0-25° C. Compounds offormula II may be prepared by the methods described in applicationWO99/03859.

Compounds of formula II wherein X represents OSO₂CF₃ may be preparedfrom compounds of formula II wherein X represents OH by reaction withtrifluoromethanesulfonic anhydride or othertrifluoromethanesulfonylating agent in the presence of a base and asuitable solvent. Suitable bases include pyridine, and2,6-di-t-butylpyridine. The reaction is preferably performed at atemperature of −78 to 120° C., and most preferably at a temperature of−78 to 0° C.

Compounds of formula III are commercially available, are described inthe literature of synthetic organic chemistry, or may be prepared bymethods known to one skilled in the art of synthetic organic chemistry.For example, compounds of formula III in which M represents B(OH)₂ maybe prepared from suitable aromatic compounds having hydrogen or halogengroups, via conversion to the corresponding aryllithium or arylmagnesiumcompounds followed by reaction with trimethylborate and subsequenthydrolysis of the resulting borate ester. Similarly, suitable aromaticcompounds having hydrogen or halogen groups may be converted tocompounds of formula III in which M represents a trialkylstannyl groupvia conversion to the corresponding aryllithium or arylmagnesiumcompounds followed by reaction with an appropriate trialkylstannylhalide. The formation of the aryllithium or arylmagnesium compound isperformed in a suitable inert solvent, for example, tetrahydrofuran.Alternatively, suitable aromatic compounds having halogen or OSO₂CF₃ maybe converted to compounds of formula III in which M represents B(OH)₂via reaction with bis(pinacolato)diboron and an organometallic catalyst,followed by hydrolysis of the resulting borate ester, or to compounds offormula III in which M represents a trialkylstannyl group via reactionwith the appropriate bis(trialkyltin) in the presence of a suitableorgnometallic catalyst. The reaction is performed in a suitable inertsolvent, for example tetrahydrofuran, and suitable organometalliccatalyst include, for example tetrakis(triphenylphosphine). The reactionis performed at a temperature of about 0° C. to about 150° C.,preferably about 20° C. to about 100° C. For typical procedures foreffecting such conversions, see, for example, Organic Syntheses, 1963,Coll. Vol. 4, 68; J. Org. Chem. 1995, 60, 7508.

An alternative synthesis of compounds of formula I is outlined in Scheme2. Unless otherwise noted Ar, R, M and X in Scheme 2 are as definedabove for Scheme 1, and Ar and R are as defined in Formula I. Theconditions for effecting the preparation described in Scheme 2 would besimilar to those under which the preparations described in Scheme 1would be performed with corresponding M and X groups.

Compounds of formula IV in which M represents B(OH)₂ may be preparedfrom compounds of formula II in which X is halogen, via conversion tothe corresponding aryllithium or arylmagnesium compounds followed byreaction with trialkylborate and subsequent hydrolysis of the resultingborate ester. Similarly, compounds of formula IV in which M representsSnR³ ₃ and R³ represents a C₁-C₆ alkyl group may be prepared fromcompounds of formula II in which X is halogen, via conversion to thecorresponding aryllithium or arylmagnesium compounds followed byreaction with an appropriate trialkylstannyl halide. The formation ofthe aryllithium or arylmagnesium compound is performed in a suitableinert solvent, for example, tetrahydrofuran, and Alternatively,compounds of formula IV in which M represents B(OH)₂ may be preparedfrom compounds of formula II in which X represents halogen or OSO₂CF₃via reaction with bis(pinacolato)diboron and an organometallic catalyst,followed by hydrolysis of the resulting borate ester, and compounds offormula IV in which M represents represents SnR³ ₃ and R³ represents aC₁-C₆ alkyl group may be prepared from compounds of formula II in whichX represents halogen or OSO₂CF₃ via reaction with the appropriatebis(trialkyltin) R³ ₃SnSnR³ ₃ in the presence of a suitableorgnometallic catalyst. The reaction is performed in a suitable inertsolvent, for example tetrahydrofuiran, and suitable organometalliccatalyst include, for example tetrakis(triphenylphosphine). The reactionis performed at a temperature of about 0° C. to about 150° C.,preferably about 20° C. to about 100° C. For typical procedures foreffecting such conversions, see, for example, Organic Syntheses, 1963,Coll. Vol. 4, 68; J. Org. Chem. 1995, 60, 7508.

It will be appreciated by one skilled in the art that certain optionalaromatic substituents in the compounds of the invention may beintroduced by employing aromatic substitution reactions, or functionalgroup transformations to modify an existing substituent, or acombination thereof. Such reactions may be effected either prior to orimmediately following the processes mentioned above, and are included aspart of the process aspect of the invention. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic flnctionalisation of an aromatic ring, for example vianitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example via reduction, such as by catalytichydrogenation; acylation, alkylation, sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup via conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group, for example vianucleophilic or organometallically-catalysed substitution reactions.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

The above-described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

Unless otherwise stated, the above-described reactions are conductedunder an inert atmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts. Acid additionsalts of compounds of formula I may be formed by reacting the free baseor a salt, enantiomer or 0protected derivative thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, e.g., water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuum or by freeze drying. The reaction may be ametathetical process or it may be carried out on an ion exchange resin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallisation, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemisation.

Pharmacology

The pharmacological activity of compounds of the invention may bemeasured using the tests set out below:

Test A—Assay for Affinity at α7 nAChR Subtype

[¹²⁵I]-α-Bungarotoxin (BTX) bindings, to rat hiipocam]2al membranes. Rathippocampi were homogenized in 20 volumes of cold homogenization buffer(HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000 g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000 g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pretreating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Nonspecific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the α4 nAChR subtype

[³H]-(−)-nicotine binding. Using a procedure modified fromMartino-Barrows and Kellar (Mol Pharm (1987) 31:169-174), rat brain(cortex and hippocampus) was homogenized as in the [¹²⁵I]α-BTX bindingassay, centrifuged for 20 minutes at 12,000×g, washed twice, and thenresuspended in HB containing 100 μM diisopropyl fluorophosphate. After20 minutes at 4° C., membranes (approximately 0.5 mg) were incubatedwith 3 nM [³H]-(−)-nicotine, test drug, 1 μM atropine, and either 2 mMCaCl₂ or 0.5 mM EGTA for 1 h at 4° C., and then filtered over Whatmanglass fiber filters (thickness C) (pretreated for 1 h with 0.5% PEI)using a Brandel cell harvester. Nonspecific binding was described by 100μM carbachol, and specific binding was typically 84%.

Binding data analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (nH) were calculated using thenon-linear curve-fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding KD values of 1.67 and1.70 nM for the [¹²⁵I]-α-BTX and [3H]-(−)-nicotine ligands respectively.Ki values were estimated using the general Cheng-Prusoff equation:Ki−[IC₅₀]/((2+([ligand]/[KD])n)1/n−1)where a value of n=1 was used whenever nH<1.5 and a value of n=2 wasused when nH≧1.5. Samples were assayed in triplicate and were typically±5%. Ki values were determined using 6 or more drug concentrations. Thecompounds of the invention are compounds with binding affinities (Ki) ofless than 1000 nM in either Test A or Test B, indicating that they areexpected to have useful therapeutic activity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

EXAMPLES

Commercial reagents were used without fuirther purification.n-Butyllithium was used as a solution in hexane. Mass spectra wererecorded using an HPLC-MS system employing a HP-1100 HPLC and aMicromass LCZ Mass Spectrometer using APCI as the ionization technique,and are reported as m/z for the parent molecular ion. Room temperaturerefers to 20-25° C.5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and other precursors were prepared as described in international patentapplication WO 99/03859. Radiolabelled forms of compounds of theexamples are useful in a screen for the discovery of novel medicinalcompounds which bind to and modulate the activity, via agonism, partialagonism, or antagonism, of the α7 nicotinic acetylcholine receptor. Suchradiolabelled compounds are synthesized either by incorporatingradiolabelled starting materials or, in the case of tritium, exchange ofhydrogen for tritium by known methods. Known methods include (1)electrophilic halogenation, followed by reduction of the halogen in thepresence of a tritium source, for example, by hydrogenation with tritiumgas in the presence of a palladium catalyst, or (2) exchange of hydrogenfor tritium performed in the presence of tritium gas and a suitableorganometallic (e.g. palladium) catalyst.

Example 1(2′R)-5′-(Thiazol-5-yl)srpiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 5-Tri-n-butylstannylthiazole

n-Butyllithium (1.6M, 4.95 mL, 7.88 mmol) was added to a solution of2-trimethylsilylthiazole (826 mg, 5.25 mmol) in anhydrous ether (45 mL)stirred at −78° C. under nitrogen. After 20 min, tri-n-butylstannylchloride (2.57 g, 7.88 mmol) was added, then the solution was allowed towarm to room temperature, and stirred for another 1 h. The mixture wasquenched and washed with 1N sodium hydroxide, dried through MgSO₄, andthen the solvent was evaporated to give a brown oily residue. Theresidue of 2-trimethylsilyl-5-tributylstannyl-thiazole was passedthrough a column of neutral alumina eluting with a gradient ofarnrunoniated methanol in chloroform to give the sub-title compound as ayellow oil (1.5 g).

(b)(2′R)-5′-(Thiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b)pyridine](89 mg, 0.3 mmol), 5-tri-n-butylstannylthiazole (390 mg, 1.05 mmol) andtetrakis(triphenylphosphine)palladium (0) (36 mg, 0.03 mmol) weredissolved in toluene (6 mL) and sealed under nitrogen. The mixture wasstirred and microwaved at 135° C. under nitrogen for 8 min. The mixturewas filtered through diatomaceous earth. The filtrate was diluted withchloroform, and the chloroform layer solution was washed with saturatedsodium bicarbonate, dried through MgSO₄, then filtered, and evaporated.The compound was purified by flash chromatography using a gradient ofammoniated methanol in chloroform, followed by reverse phase HPLC on aWaters Novapak-HR C₁₈ Column using a gradient of 0-65%acetonitrile/water (each solvent containning 0.1% trifluoroacetic acidas a buffer) as the eluant. The product-containing collections wereevaporated. The residue was dissolved in methanol, then excess 1Nhydrochloric acid was added, and the solvent was evaporated to give thedihydrochloride salt of the title compound (79 mg) as a colourlesssolid; m/e 300 (MH⁺).

Example 2(2′R)-5′-(Thiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 4-Tri-n-butylstannylthiazole

n-Butyllithium (1.6M, 3.1 mL, 4.94mmol) was added to a solution of2,4-dibromothiazole (1 g, 4.12 mmol) in anhydrous ether (25 mL) stirredat −78° C. under nitrogen. After 15 min, chlorotrimethylsilane (493 mg,4.53 mmol) was added, then the solution was allowed to warm to roomtemperature, and stirred for another I h. The mixture was quenched, andwashed with 1N sodium hydroxide, dried through MgSO₄, and then thesolvent was evaporated to give a brown oily residue (905 mg). Theresidue was purified by the distillation to give4-bromo-2-trimethylsilylthiazole (650 mg) as a light-brown oil. Undernitrogen, the 4-bromo-2-trimethylsilylthiazole (340 mg, 1.44 mmol) wasthen dissolved in anhydrous ether (15 mL), and the resulting solutionwas stirred at −78° C. n-Butyllithium (1.5M, 1.4 mL, 2.16 mmol) wasadded, and the resulting solution was stirred at −78 ° C. for 30minutes. Tri-n-butylstannyl chloride (703 mg, 2.16 mmol) was added, thenthe solution was allowed to warm to room temperature, and stirred foranother lh. The mixture was quenched and washed with 1N sodiumhydroxide, dried through MgSO₄, and then the solvent was evaporated togive a brown oily residue. The residue of2-trimethylsilyl-4-tri-n-butylstannylthiazole was passed through acolumn of neutral alumina eluting with a gradient of ammoniated methanolin chloroform to give the sub-title compound,4-tri-n-butylstannylthiazole as a yellow oil (330 mg).

(b)(2′R)-5′-(Thiazol-4-yl)srpiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b)pyridine]

Prepared by a method analogous to that described for the preparation ofExample 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine)and 4-tri-n-butylstannylthiazole. The compound was isolated as thedihydrochloride salt which was a colourless solid; m/e 300 (MH⁺).

Example 3(2′R)-5′-(Thiazol-2-yl)spiro[1-azabicyclo[2.2.2loctane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 2-Tri-n-butylstannylthiazole

n-Butyllithium (1.6M, 5.3 mL, 8.37 mmol) was added to a solution ofthiazole (450 mg, 5.23 mmol) in anhydrous ether (30 mL) stirred −78° C.under nitrogen. After 30 min tri-n-butylstannyl chloride (2.73 g, 8.37mmol) was added, then the solution was allowed to warm to roomtemperature, and stirred for another 1 h. The mixture was quenched andwashed with 1N sodium hydroxide, dried through MgSO₄, and then thesolvent was evaporated to give the sub-title compound a brown oilyresidue (2.0 g), which was used in the next step without furtherpurification.

(b)(2′R)-5′-(Thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 2-tri-n-butylstannylthiazole. The title compound was isolated as thedihydrochloride salt which was a colourless solid; m/e 300 (MH⁺).

Example 4(2′R)-5′-(2-Methylthiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 2-Methyl-4-triethylstannyl-thiazole

n-Butyllithium (1.6M, 3.3 mL, 5.35 mmol) was added to a solution of2,4-dibromothiazole (1.0 g, 4.12 mmol) in anhydrous ether (10 mL)stirred at −78 ° C. under nitrogen. After 20 minutes, methyltrifluromethanesulfonate (878 mg, 5.35 mmol) was added, then thereaction mixture was allowed to warm to room temperature, and stirredfor another 1 h. The mixture was quenched and washed with water, washedwith brine, dried through MgSO₄, and then the solvent was evaporated togive a brown oily residue of 2-methyl-4-bromo-thiazole (900 mg). Undernitrogen, the 2-methyl-4-bromo-thiazole (430 mg, 2.42 mmol) dissolved inanhydrous ether (5 mL) then cooled to −78° C. under nitrogen.n-Butyllithium (1.6M, 1.7 mL, 2.66 mmol) was added, followed, after 10min by triethylstannyl bromide (760 mg, 2.66 mmol). The solution wasthen warmed to room temperature, and stirred for another 1 h. Themixture was quenched, and washed with 1N sodium hydroxide, dried throughMgSO₄, and then the solvent was evaporated to give the sub-titlecompound give as a brown oily residue (655 mg), which was used withoutfurther purification in the next step.

(b)(2′R)-5′-(2-Methylthiazol-4-yl)spiro[1-azabicyclo[2.2.2octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 2-methyl-4-triethylstannyl-thiazole. The title compound was obtainedas a colourless solid; mn/e 314 (MH⁺).

Example 5(2′R)-5′-(Benzothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3.2′(3′H)-furo[2,3-b]pyridine]

(a) 2-Tri-n-butylstannylbenzothiazole

n-Butyllithium (1.6M, 10 mL, 15.98 mmol) was added to a solution ofbenzothiazole (1.80 g, 13.3 mmol) in anhydrous ether (30 ml) stirred at−78° C. under nitrogen. After 10 min, tri-n-butylstannyl chloride (4.33g, 13.31 mmol) was added, then the solution was allowed to warm to roomtemperature, and stirred for another 1 h. The mixture was quenched andwashed with 1N sodium hydroxide, dried through MgSO₄, filtered, andevaporated to give the sub-title compound as a brown oily residue (5.0g), which was used without further purification in the next step.

(b)(2′R)-5′-(Benzothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-bpyridine]and 2-tri-n-butylstannylbenzothiazole. The title compound was obtainedas a colourless solid; m/e 350 (MH⁺).

Example 6(2′R)-5′-(Oxazol-2-yl)spiro[1-azabicyclo]2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine

(a) 2-Triethylstannyloxazole

n-Butyllithium (1.6M, 11 mL, 17.38 mmol) was added to a solution ofoxazole (1.0 g, 14.48 mmol) in anhydrous ether (20 mL) stirred at −78°C. under nitrogen. After 5 min, triethylstannyl bromide (2.07 g, 7.24mmol) was added, then the reaction mixture was allowed to warm to roomtemperature, and stirred for another 1 h. The mixture was quenched, andwashed with 1N sodium hydroxide, dried through MgSO₄, and then thesolvent was evaporated to give the sub-title compound as a brown oilyresidue (1.0 g), which was used without fuirther purification in thenext step.

(b)(2′R)-5′-(Oxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 1 from(2′R)-5′-bromo-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 2-triethylstannyloxazole. The dihydrochloride salt of the titlecompound was obtained as a colourless solid; m/e 284 (MH⁺).

Example 7(2′R)-5′-(Benzoxazol-2-yl)spiro[1-azabicyclo[2.2.2]oxtane-3,2′(3′H)-fro[2,3-b]pyridine]

(a) 2-Triethylstannylbenzoxazole

n-Butyllithium (1.6M, 6.0 mL, 9.57 mmol) was added to a solution ofbenzoxazole (950 mg, 7.98 mmol) in anhydrous ether (20 mL) stirred at−78° C. under nitrogen. After 10 min, triethylstannyl bromide (2.28 g,7.98 mmol) was added, then the reaction mixture was allowed to warm toroom temperature, and stirred for another 1 h. The mixture was quenched,and washed with 1N sodium hydroxide, dried through MgSO₄, and then thesolvent was evaporated to give the sub-title compound as a brown oilyresidue which was used directly without further purification for thenext step.

(b)(2′R)-5′-(Benzoxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analog to that described for the preparation ofExample 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 2-triethylstannylbenzoxazole. The dihydrochloride salt of the titlecompound was obtained as a colourless solid; m/e 343 (MH⁺).

Example 8(2′R)-5′-(3,5-Dimethylisoxazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](200 mg, 0.68 mmol), and 3,5-dimethyl-isoxazole-4-boronic acid (106 mg,0.75 mmol), tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.017mmol) and sodium carbonate (305 mg, 2.21 mmol) were placed in a sealedtube under nitrogen. Water (1.2 mL), ethanol (1.5 mL) and ethyleneglycol dimethyl ether (5.5 mL) was added. The mixture was stirred andheated at 100° C. under nitrogen overnight. The mixture was filteredthrough diatomaceous earth. The filtrate was diluted with chloroform,washed with saturated sodium bicarbonate, dried through MgSO₄, and thenthe solvent was evaporated. The compound was purified by flashchromatography using a gradient of ammoniated methanol in chloroformfollowed by reverse phase HPLC on a Waters Novapak-HR C₁₈ Column using agradient of 0-65% acetonitrile/water (each solvent containning 0.1%trifluoroacetic acid as a buffer) as the eluant. The product-containingcollections were evaporated. The residue was dissolved in methanol, thenexcess 1N hydrochloric acid was added, and the solvent was evaporated togive the dihydrochloride salt of the title compound (75 mg) as a whitesolid; m/e 313 (MH⁺).

1. A compound having the formula:

and pharmaceutically-acceptable salts thereof, wherein Ar is either amonocyclic 5-membered ring heterocycle or a bicyclic benzo-fused5-membered ring heterocycle connected via the 5-membered ring, having,as part of the five membered ring one ring nitrogen atom and either onering oxygen atom or one ring sulfur atom, said monocyclic or fusedbicyclic ring heterocycle being substituted with 0, 1, or 2substitutents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ halogenatedalkyl, C₁₋₄ oxygenated alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halogen, —CO₂R¹,—C(O)R¹, —CN, —NO₂, —(CH₂)_(n)NR¹R² n is 0, 1, or 2 R¹ and R² areindependently selected at each occurrence from hydrogen or C₁₋₄alkyl Ris a substitutent selected from hydrogen, C₁₋₄alkyl, C₁₋₄ halogenatedalkyl, C₁₋₄ oxygenated alkyl, or halogen.
 2. A compound according toclaim 1 or a pharmaceutically-acceptable salt thereof, wherein: Ar is a5-membered ring heterocycle having one ring nitrogen atom and either onering oxygen atom or one ring sulfur atom and having 0 or 1 substituentsselected from methyl, ethyl, or halogen, and R is hydrogen.
 3. Acompound according to claim 1, selected from:(2′R)-5′-(thiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(thiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2-methylthiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(benzothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(oxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(benzoxazol-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(3,5-dimethylisoxazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2-trifluoromethylthiazol-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2-methylthiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine],or(2′R)-5′-(2-trifluoromethylthiazol-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].4. A pharmaceutical composition comprising a compound according to claim1, and a pharmaceutically-acceptable diluent or carrier. 5-13.(canceled)
 14. A method of treatment or prophylaxis of human diseases orconditions in which activation of the α₇ nicotinic receptor isbeneficial which comprises administering a therapeutically effectiveamount of a compound according to claim
 1. 15. A method of treatment orprophylaxis of psychotic disorders or intellectual impairment disorders,which comprises administering a therapeutically effective amount of acompound according to claim
 1. 16. The method according to claim 15,wherein said psychotic disorder is Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder Parkinson's disease, Huntington'sdisease, Tourette's syndrome, a neurodegenerative disorder in whichthere is loss of cholinergic synapses anxiety, schizophrenia or mania ormanic depression.
 17. A method of treatment or prophylaxis of jetlag,cessation of smoking, nicotine addiction, craving, pain, and forulcerative colitis, which comprises administering a therapeuticallyeffective amount of a compound according to claim
 1. 18. A compoundaccording to claim 1, wherein one or more of the atoms is a radioisotopeof the element.
 19. A compound according to claim 18, wherein theradioisotope is tritium.
 20. (canceled)